binds many growth factors through its long heparan sulfate side-chains. Yet, long heparan sulfate chains interfere with lacritin binding. Since syndecans are always decorated with heparan sulfate, this means that heparanase must be available to partially or completely cleave off heparan sulfate, allowing lacritin to bind. Indeed, no binding was detected from cells lacking heparanase after siRNA depletion. Binding was restored by spiking in exogenous heparanase or heparitinase. Thus, heparanase regulates lacritin function as an 'on-switch'. Exposed 3-O sulfated groups on heparanase-cleaved heparan sulfate (that likely interacts with the cationic face of lacritin's C-terminal amphipathic alpha helix), and an N-terminal chondroitin sulfate chain (likely also binds to the cationic face) appear to contribute to binding. Point mutagenesis of lacritin has narrowed the ligation site. This novel heparanase mechanism appears at first glance to be poor for ocular health since heparanase release from invading lymphocytes in the corneal stroma is inflammatory. Yet heparanase is a normal secretory product of the corneal epithelium. Lacritin-dependent mitogenesis is inhibitable by pertussis toxin,. The implication is that another key element of lacritin targeting specificity is a G-protein-coupled receptor that would presumably form a cell surface targeting complex with SDC1. Involvement of a G-protein coupled receptor would explain the rapidity of lacritin signaling. Function Lacritin is a glycoprotein of the human tear film, and to a lesser extent of saliva, lung lavage and plasma. It is mainly produced by the lacrimal gland. Some lacritin also is produced by the meibomian gland, and also by epithelial cells of the conjunctiva and cornea. The lacritin gene (LACRT) is one of the most transcriptionally regulated genes in the human eye. Functional studies suggest a role in epithelial renewal of some non-germative epithelia. By flowing downstream through ducts, it may generate a 'proliferative field'. Lacritin also promotes secretion (including that of lipocalin-1 and lactoferrin), cell survival and regeneration of the corneal epithelium after wounding. Three times daily topical treatment with C-terminal lacritin synthetic peptide 'Lacripep' (also known as 'N-94/C-6') at a 4 µM concentration regenerated corneal nerves and the ocular surface epithelium in the mouse Aire-/- dry eye model. This raises the possibility that lacritin may have clinical applications in the treatment of dry eye, the most common eye disease. It also may be beneficial in promoting healing after LASIK or PRK surgery. Recent studies suggest that lacritin monomer is differentially down regulated in not only in dry eye, but